UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Synaptotagmin oligomerization is essential for calcium control of regulated exocytosis

Bello, OD; Jouannot, O; Chaudhuri, A; Stroeva, E; Coleman, J; Volynski, KE; Rothman, JE; (2018) Synaptotagmin oligomerization is essential for calcium control of regulated exocytosis. Proceedings of the National Academy of Sciences of the United States of America , 115 (32) E7624-E7631. 10.1073/pnas.1808792115. Green open access

[thumbnail of Bello et al_Manuscript_Complete.pdf]
Preview
Text
Bello et al_Manuscript_Complete.pdf - Accepted Version

Download (1MB) | Preview

Abstract

Regulated exocytosis, which underlies many intercellular signaling events, is a tightly controlled process often triggered by calcium ion(s) (Ca2+). Despite considerable insight into the central components involved, namely, the core fusion machinery [soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)] and the principal Ca2+ sensor [C2-domain proteins like synaptotagmin (Syt)], the molecular mechanism of Ca2+-dependent release has been unclear. Here, we report that the Ca2+-sensitive oligomers of Syt1, a conserved structural feature among several C2-domain proteins, play a critical role in orchestrating Ca2+-coupled vesicular release. This follows from pHluorin-based imaging of single-vesicle exocytosis in pheochromocytoma (PC12) cells showing that selective disruption of Syt1 oligomerization using a structure-directed mutation (F349A) dramatically increases the normally low levels of constitutive exocytosis to effectively occlude Ca2+-stimulated release. We propose a parsimonious model whereby Ca2+-sensitive oligomers of Syt (or a similar C2-domain protein) assembled at the site of docking physically block spontaneous fusion until disrupted by Ca2+ Our data further suggest Ca2+-coupled vesicular release is triggered by removal of the inhibition, rather than by direct activation of the fusion machinery.

Type: Article
Title: Synaptotagmin oligomerization is essential for calcium control of regulated exocytosis
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.1808792115
Publisher version: http://dx.doi.org/10.1073/pnas.1808792115
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: PC12 cells, SNARE protein, calcium, regulated exocytosis, synaptotagmin
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy
URI: https://discovery.ucl.ac.uk/id/eprint/10053847
Downloads since deposit
69Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item